Abstract
ARG2 has been reported to inhibit autophagy in vascular endothelial cells and keratinocytes. However, studies of its mechanism of action, its role in skin fibroblasts, and the possibility of promoting autophagy and inhibiting cellular senescence through ARG2 inhibition are lacking. We induced cellular senescence in dermal fibroblasts by using H2O2. H2O2-induced fibroblast senescence was inhibited upon ARG2 knockdown and promoted upon ARG2 overexpression. The microRNA miR-1299 suppressed ARG2 expression, thereby inhibiting fibroblast senescence, and miR-1299 inhibitors promoted dermal fibroblast senescence by upregulating ARG2. Using yeast two-hybrid assay, we found that ARG2 binds to ARL1. ARL1 knockdown inhibited autophagy and ARL1 overexpression promoted it. Resolvin D1 (RvD1) suppressed ARG2 expression and cellular senescence. These data indicate that ARG2 stimulates dermal fibroblast cell senescence by inhibiting autophagy after interacting with ARL1. In addition, RvD1 appears to promote autophagy and inhibit dermal fibroblast senescence by inhibiting ARG2 expression. Taken together, the miR-1299/ARG2/ARL1 axis emerges as a novel mechanism of the ARG2-induced inhibition of autophagy. Furthermore, these results indicate that miR-1299 and pro-resolving lipids, including RvD1, are likely involved in inhibiting cellular senescence by inducing autophagy.
Highlights
This study aimed to investigate the inhibition of autophagy by ARG2, the target of miR-1299 in dermal fibroblast senescence, and the action of the pro-resolving Resolvin D1 (RvD1) in the downregulation of ARG2 that results in cell senescence inhibition
These results suggest the possibility that RvD1 inhibits senescence by inducing autophagy via ARL1 downregulation of ARG2
The presented study reports whether the miR-1299 target ARG2 is involved in fibroblast senescence through its autophagy inhibitory action, its mechanism of action, and the effect of RvD1 as an inhibitor of ARG2 expression
Summary
Autophagy is a physiological process that regulates the breakdown and recycling of waste as well as of damaged intracellular components through lysosomal activity. The regulation of autophagy plays an essential role in tissue homeostasis and aging [1]. The suppression of autophagy is regarded as a phenotype of aging [2]. Autophagyrelated proteins, such as Atg, Atg, and beclin, are expressed at lower levels in the aged human brain than in the young brain [3]. Urothrin-A–induced mitophagy and caloric-restriction-induced autophagy have been reported to prolong lifespan and maintain health [4,5,6]
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